The present invention relates to a novel composition and a method for improving the pharmacokinetics of drugs which are metabolized by cytochrome P450 monooxygenase. In addition, the present invention relates to a novel composition and a method for inhibiting retroviral proteases and in particular for inhibiting human immunodeficiency virus (HIV) protease and a composition and a method for inhibiting a retroviral infection, in particular an HIV infection.
Infection by the retrovirus known as human immumodeficiency virus (HIV) continues to be a serious human health problem. Methods for treating HIV infections include administering agents which inhibit the activity of viral enzymes which are essential to the life cycle of the virus.
The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See Wellink, Arch. Virol. 98 1 (1988). Retroviral proteases most commonly process the gag precursor into core proteins, and also process the pol precursor into reverse transcriptase and retroviral protease. Retroviral proteases are known to be sequence specific. See Pearl, Nature 328 482 (1987).
The correct processing of the precursor polyproteins by the retroviral protease is necessary for the assembly of infectious virions. It has been shown that in vitro mutagenesis that produces protease-defective virus leads to the production of immature core forms which lack infectivity. See Crawford, J. Virol. 53 899 (1985); Katoh, et al., Virology 145 280 (1985). Therefore, retroviral protease inhibition provides an attractive target for antiviral therapy. See Mitsuya, Nature 325 775 (1987).
It has recently been disclosed that the HIV protease inhibitor ritonavir (also known as ABT-538) is effective in humans for inhibiting an HIV infection.
It has also been discovered that ritonavir is an inhibitor of the metabolic enzyme cytochrome P450 monooxygenase.
Some drugs and, in particular, some HIV protease inhibitors are metabolized by cytochrome P450 monooxygenase, leading to unfavorable pharmacokinetics and the need for more frequent and higher doses than are most desirable. Administration of such drugs with an agent that inhibits metabolism by cytochrome P450 monooxygenase will improve the pharmacokinetics (i.e., increase half-life, increase the time to peak plasma concentration, increase blood levels) of the drug.
It has been discovered that coadministration of ritonavir with a drug which is metabolized by cytochrome P450 monooxygenase, especially the P450 3A4 isozyme, causes an improvement in the pharmacokinetics of such a drug.
In particular, it has been discovered that coadministration of ritonavir with an HIV protease inhibitor which is metabolized by cytochrome P450 monooxygenase causes an unexpected improvement in the pharmacokinetics of such an HIV protease inhibitor.